This is the final resubmission for the K07 award. Candidate: Tianying Wu has a unique academic background, with a PhD in nutrition biochemistry and postdoctoral training in nutrition and molecular epidemiology at the Harvard School of Public Health, where she also earned a master's degree in epidemiology. She is currently an Assistant Professor at the University of Cincinnati Medical Center. This award will provide Dr. Wu with a valuable opportunity to enhance her knowledge of cancer epidemiology and cancer biology and to acquire advanced statistical skills. Thus, this award will enable her to become an independent cancer epidemiologist with a rare combination of skills that can bring new insights to the field of cancer etiology. Research: Oxidative stress is hypothesized to play an important role in prostate cancer (PCa) development and progression, but no large epidemiologic studies have proven this association. This gap exists because the oxidative stress scenario is complex; traditional oxidation markers are unstable and cannot maximally capture oxidative stress from many sources. To address this gap, we will use fluorescent oxidation products, a novel, global oxidative stress marker that is stable and can maximally reflect oxidative stress from different sources. Measuring global oxidation will form the basis for better estimation of the contributions of individual oxidative stress pathways such as the nitric oxide (NO)-induced and glycoxidative-induced pathways. Further, oxidative stress may be modifiable through diet; however, a dietary pattern specifically associated with oxidation has not been characterized. The unifying hypothesis is that increased levels of global oxidative stress will be associated with increased risk of PCa. Glycoxidative stress will predict the aggressiveness of PCa; however, this association is modified by the levels of FLOP. We also hypothesize that moderate to high levels of nitric oxide will be associated with a lower risk of PCa, when global oxidative stress is low. This hypothesis will be tested comprehensively by completion of the following specific aims using the Health Professionals Follow-up Study (HPFS): (1) examination of oxidative stress in relation to PCa using a prospective nested case-control design, (2) exploration of key dietary predictors of oxidation markers using reduced rank regression models, and determination of the association between the created dietary score and incidence of PCa in the whole HPFS cohort, and (3) accurate quantification of complex oxidation- PCa associations using structural equation models. Public Health Implications: (1) Prostate-specific antigen (PSA) screening has low specificity but high sensitivity. Our goal is to complement PSA screening. Instead of screening all men in the same manner regardless of their long-term risk, we will identify each person's estimated risk for PCa based on his global and specific oxidative stress levels in addition to his PSA results. This will identify individuals in need of aggressive treatment and will avoid overtreatment. (2) Predicting the effects of oxidative stress is of great interest, as oxidative stress levels may be modifiable.